[Banxia Xiexin Decoction inhibiting colitis-associated colorectal cancer infected with Fusobacterium nucleatum by regulating Wnt/ß-catenin pathway].

This paper investigates the intervention effect and mechanism of Banxia Xiexin Decoction(BXD) on colitis-associated colorectal cancer(CAC) infected with Fusobacterium nucleatum(Fn). C57BL/6 mice were randomly divided into a control group, Fn group, CAC group [azoxymethane(AOM)/dextran sulfate sodium salt(DSS)](AOM/DSS), model group, and BXD group. Except for the control and AOM/DSS groups, the mice in the other groups were orally administered with Fn suspension twice a week. The AOM/DSS group, model group, and BXD group were also injected with a single dose of 10 mg·kg~(-1) AOM combined with three cycles of 2.5% DSS taken intragastrically. The BXD group received oral administration of BXD starting from the second cycle until the end of the experiment. The general condition and weight changes of the mice were monitored during the experiment, and the disease activity index(DAI) was calculated. At the end of the experiment, the colon length and weight of the mice in each group were compared. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the colon tissue. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of interleukin(IL)-2, IL-4, and IL-6 inflammatory factors in the serum. Immunohistochemistry(IHC) was used to detect the expression of Ki67, E-cadherin, and ß-catenin in the colon tissue. Western blot was used to detect the protein content of Wnt3a, ß-catenin, E-cadherin, annexin A1, cyclin D1, and glycogen synthase kinase-3ß(GSK-3ß) in the colon tissue. The results showed that compared with the control group, the Fn group had no significant lesions. The mice in the AOM/DSS group and model group had decreased body weight, increased DAI scores, significantly increased colon weight, and significantly shortened colon length, with more significant lesions in the model group. At the same time, the colon histology of the model group showed more severe adenomas, inflammatory infiltration, and cellular dysplasia. The levels of IL-4 and IL-6 in the serum were significantly increased, while the IL-2 content was significantly decreased. The IHC results showed low expression of E-cadherin and high expression of Ki67 and ß-catenin in the model group, with a decreased protein content of E-cadherin and GSK-3ß and an increased protein content of Wnt3a, ß-catenin, annexin A1, and cyclin D1. After intervention with BXD, the body weight of the mice increased; the DAI score decreased; the colon length increased, and the tumor decreased. The histopathology showed reduced tumor proliferation and reduced inflammatory infiltration. The levels of IL-6 and IL-4 in the serum were significantly decreased, while the IL-2 content was increased. Meanwhile, the expression of E-cadherin was upregulated, and that of Ki67 and ß-catenin was downregulated. The protein content of E-cadherin and GSK-3ß increased, while that of Wnt3a, ß-catenin, annexin A1, and cyclin D1 decreased. In conclusion, BXD can inhibit CAC infected with Fn, and its potential mechanism may be related to the inhibition of Fn binding to E-cadherin, the decrease in annexin A1 protein level, and the regulation of the Wnt/ß-catenin pathway.

High-dose ascorbate exerts anti-tumor activities and improves inhibitory effect of carboplatin through the pro-oxidant function pathway in uterine serous carcinoma cell lines.

OBJECTIVE: Uterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells. METHODS: Cell proliferation was evaluated by MTT and colony formation assays in ARK1, ARK2 and SPEC2 cells. Cellular stress, antioxidant ability, cleaved caspase 3 activity and adhesion were measured by ELISA assays. Cell cycle was detected by Cellometer. Invasion was measured using a wound healing assay. Changes in protein expression were determined by Western immunoblotting. RESULTS: High-dose ascorbate significantly inhibited cell proliferation, caused cell cycle arrest, induced cellular stress, and apoptosis, increased DNA damage, and suppressed cell invasion in ARK1 and SPEC2 cells. Treatment of both cells with 1 mM N-acetylcysteine reversed ascorbate-induced apoptosis and inhibition of cell proliferation. The combination of ascorbate and carboplatin produced significant synergistic effects in inhibiting cell proliferation and invasion, inducing cellular stress, causing DNA damage, and enhancing cleaved caspase 3 levels compared to each compound alone in both cells. CONCLUSIONS: Ascorbate has potent antitumor activity and acts synergistically with carboplatin through its pro-oxidant effects. Clinical trials of ascorbate combined with carboplatin as adjuvant treatment of uterine serous carcinoma are worth exploring.

Banxia Xiexin Decoction delays colitis-to-cancer transition by inhibiting E-cadherin/ß-catenin pathway via Fusobacterium nucleatum FadA.

ETHNOPHARMACOLOGICAL RELEVANCE: Colitis is an important risk factor for the occurrence of colorectal cancer (CRC), and the colonization of Fusobacterium nucleatum (Fn) in the intestines accelerates this transformation process. Banxia Xiexin Decoction (BXD), originating from Shanghanlun, is a classic prescription for treating gastrointestinal diseases. Current researches indicate that BXD can effectively delay the colitis-to-cancer transition, but it is still unclear whether it can inhibit Fn colonization to achieve this delaying effect. AIM OF STUDY: This study explored the effect and mechanism of BXD in inhibiting Fn intestinal colonization to delay colitis-to-cancer transition. MATERIALS AND METHODS: We constructed a mouse model of colitis-to-cancer transition by regularly gavaging Fn combined with azoxymethane (AOM)/dextran sodium sulfate (DSS), and administered BXD by gavage. We monitored the body weight of mice, measured the length and weight of their colons, and calculated the disease activity index (DAI) score. The growth status of colon tumors was observed by hematoxylin and eosin (H&E) staining, and the changes in gut microbiota in each group of mice were detected by 16S rDNA analysis. Immunohistochemistry was used to detect the expression of E-cadherin and ß-catenin in colon tissues, and immunofluorescence was used to observe the infiltration of M2 macrophages in colon tissues. In cell experiments, we established a co-culture model of Fn and colon cancer cells and intervened with BXD-containing serum. Malignant behaviors such as cell proliferation, invasion, and migration were detected, as well as changes in their cell cycle. We examined the protein levels of E-cadherin, ß-catenin, Axin2, and Cyclin D1 in each group were detected by Western blot. We used US1 strain (fadA-) as a control and observed the effects of BXD-containing serum on Fn attachment and invasion of colon cancer cells through attachment and invasion experiments. RESULTS: BXD can inhibit the colitis-to-cancer transition in mice infected with Fn, reduce crypt structure damage, improve gut microbiota dysbiosis, upregulate E-cadherin and decrease ß-catenin expression, and reduce infiltration of M2 macrophages, thus inhibiting the process of colitis-to-cancer transition. Cell experiments revealed that BXD-containing serum can inhibit the proliferation, migration, and invasion of colon cancer cells infected with Fn and regulate their cell cycle. More importantly, we found that BXD-containing serum can inhibit the binding of Fn's FadA adhesin to E-cadherin, reduce Fn's attachment and invasion of colon cancer cells, thereby downregulating the E-cadherin/ß-catenin signaling pathway. CONCLUSIONS: These findings show that BXD can inhibit Fn colonization by interfering with the binding of FadA to E-cadherin, reducing the activation of the E-cadherin/ß-catenin signaling pathway, and ultimately delaying colitis-to-cancer transition.

Synergistic inhibition effects of andrographolide and baicalin on coronavirus mechanisms by downregulation of ACE2 protein level.

The SARS-CoV-2 virus, belonging to the Coronavirus genus, which poses a threat to human health worldwide. Current therapies focus on inhibiting viral replication or using anti-inflammatory/immunomodulatory compounds to enhance host immunity. This makes the active ingredients of traditional Chinese medicine compounds ideal therapies due to their proven safety and minimal toxicity. Previous research suggests that andrographolide and baicalin inhibit coronaviruses; however, their synergistic effects remain unclear. Here, we studied the antiviral mechanisms of their synergistic use in vitro and in vivo. We selected the SARS-CoV-2 pseudovirus for viral studies and found that synergistic andrographolide and baicalein significantly reduced angiotensin-converting enzyme 2 protein level and viral entry of SARS-CoV-2 into cells compared to singal compound individually and inhibited the major protease activity of SARS-CoV-2. This mechanism is essential to reduce the pathogenesis of SARS-CoV-2. In addition, their synergistic use in vivo also inhibited the elevation of pro-inflammatory cytokines, including IL-6 and TNF-α-the primary cytokines in the development of acute respiratory distress syndrome (the main cause of COVID-19 deaths). In conclusion, this study shows that synergistic andrographolide and baicalein treatment acts as potent inhibitors of coronavirus mechanisms in vitro and in vivo-and is more effective together than in isolation.

(-)-Asarinin alleviates gastric precancerous lesions by promoting mitochondrial ROS accumulation and inhibiting the STAT3 signaling pathway.

BACKGROUND: (-)-Asarinin (Asarinin) is the primary component in the extract of the herb Asarum sieboldii Miq. It possesses various functions, including pain relief, anti-viral and anti-tuberculous bacilli effects, and inhibition of tumor growth. Gastric precancerous lesion (GPL) is a common but potentially carcinogenic chronic gastrointestinal disease, and its progression can lead to gastric dysfunction and cancer development. However, the protective effects of asarinin against GPL and the underlying mechanisms remain unexplored. METHODS: A premalignant cell model (methylnitronitrosoguanidine-induced malignant transformation of human gastric epithelial cell strain, MC cells) and a GPL animal model were established and then were treated with asarinin. The cytotoxic effect of asarinin was assessed using a CCK8 assay. Detection of intracellular reactive oxygen species (ROS) using DCFH-DA. Apoptosis in MC cells was evaluated using an annexin V-FITC/PI assay. We performed western blot analysis and immunohistochemistry (IHC) to analyze relevant markers, investigating the in vitro and in vivo therapeutic effects of asarinin on GPL and its intrinsic mechanisms. RESULTS: Our findings showed that asarinin inhibited MC cell proliferation, enhanced intracellular ROS levels, and induced cell apoptosis. Further investigations revealed that the pharmacological effects of asarinin on MC cells were blocked by the ROS scavenger N-acetylcysteine. IHC revealed a significant upregulation of phospho-signal transducer and activator of transcription 3 (p-STAT3) protein expression in human GPL tissues. In vitro, asarinin exerted its pro-apoptotic effects in MC cells by modulating the STAT3 signaling pathway. Agonists of STAT3 were able to abolish the effects of asarinin on MC cells. In vivo, asarinin induced ROS accumulation and inhibited the STAT3 pathway in gastric mucosa of mice, thereby halting and even reversing the development of GPL. CONCLUSION: Asarinin induces apoptosis and delays the progression of GPL by promoting mitochondrial ROS production, decreasing mitochondrial membrane potential (MMP), and inhibiting the STAT3 pathway.

Influence on the release of arsenic and tungsten from sediment, and effect on other heavy metals and microorganisms by ceria nanoparticle capping.

In this study, ceria nanoparticle (CNP) was used as a capping agent to investigate the efficiency and mechanism of simultaneously controlling the release of sediment internal Arsenic (As) and tungsten (W). The results of incubation experiment demonstrated that CNP capping reduced soluble As and W by 81.80% and 97.97% in overlying water, respectively; soluble As and W by 65.64% and 60.13% in pore water, respectively; and labile As and W in sediment by 45.20% and 53.20%, respectively. The main mechanism of CNP controlling sediment internal As and W was through adsorption via ligand exchange and inner-sphere complexation, as determined through adsorption experiments, XPS and FIRT spectra analysis. Besides, CNP also acted as an oxidant, facilitating the oxidation of AsⅢ to AsV and thereby enhancing the adsorption of soluble As. Additionally, sediment As and W fractions experiments demonstrated that the immobilization of As and W with CNP treatment via transforming mobile to stable fractions was another mechanism inhibiting sediment As and W release. The obtained significant positive correlation between soluble As/W and Fe/Mn, labile As/W and Fe/Mn indicated that iron (Fe) and manganese (Mn) oxidation, influenced by CNP, serve as additional mechanisms. Moreover, Fe redox plays a crucial role in controlling internal As and W, while Mn redox plays a more significant role in controlling As compared to W. Meanwhile, CNP capping effectively prevented the release of As and W by reducing the activity of microorganisms that degrade Fe-bound As and W and reduced the release risk of V, Cr, Co, Ni, and Zn from sediments. Overall, this study proved that CNP was a suitable capping agent for simultaneously controlling the release of As and W from sediment.

Efficacy and acceptability of mobile application-delivered acceptance and commitment therapy for posttraumatic stress disorder in China: A randomized controlled trial.

Due to the COVID-19 pandemic and its extensive effects, the incidence of posttraumatic stress disorder (PTSD) symptoms is rapidly increasing in China. This research aimed to assess the efficacy and acceptability of a mobile application delivering Acceptance and Commitment Therapy (ACT) in reducing PTSD symptoms. 221 Chinese individuals with elevated PTSD symptoms were randomly assigned to app-delivered ACT (ACT condition), app-delivered mindfulness (MI condition), or a waitlist (WL condition). Assessments were performed pre- and post-intervention. The results showed that participants in both the ACT and MI groups had significantly greater improvements across mental health outcomes compared to the WL group. No significant differences were observed between the ACT and MI groups except for psychological flexibility, which improved more in ACT than MI (d = -0.37). Compared to WL, the ACT group showed a greater improvement in PTSD symptoms (d = -0.79), anxiety (d = -0.62), depression (d = -0.51), posttraumatic growth (d = 0.46), and psychological flexibility (d = 0.76). The drop-out rates in the ACT and MI were 25.76% and 39.71%, respectively. Participants in the ACT condition reported medium program satisfaction. The study suggests app-delivered ACT is efficacious in reducing PTSD symptoms and improving overall mental health among Chinese adults.

Wild Rosa roxburghii Tratt Juices Grown at Different Altitudes Regulate Blood Glucose in Type 1 Diabetic Mice via the PI3K/Akt Pathway.

To explore hypoglycemic effect of wild Rosa roxburghii tratt (RRT) juice at different altitudes on type 1 diabetes mellitus (T1DM). The T1DM mouse model was induced by streptozotocin (STZ), and the experiment included a normal group (NC), model group (MC), wild RRT juice groups high (HF), medium (MF), low altitude (DF) and cultivated control group (PC). During experiment, food intake, water intake, body weight, and fasting blood glucose were measured. After 28 days of administration, glucose tolerance, glycogen level, lipid profiles, and antioxidation levels in serum and liver were measured, and histomorphological changes of liver and kidney were observed by hematoxylin and eosin staining. The results showed that wild RRT juice reduced blood glucose level, alleviated liver and kidney tissue damage, improved glucose and lipid metabolism disorders and attenuated oxidative damage in T1DM mice. Western blot showed that wild RRT juice at grown at different altitudes significantly increased protein abundance of PI3K, Akt, and GLUT2 in liver of T1DM mice. In conclusion, wild RRT juice from different altitudes improved glucose and lipid metabolism disorders and oxidative damage in T1DM mice, which may be attributed to activation of PI3K/Akt pathway. Overall effect: MF > PC > HF > DF.

Iva xanthiifolia leaf extract reduced the diversity of indigenous plant rhizosphere bacteria.

BACKGROUND: Iva xanthiifolia, native to North America, is now widely distributed in northeastern China and has become a vicious invasive plant. This article aims to probe the role of leaf extract in the invasion of I. xanthiifolia. METHODS: We collected the rhizosphere soil of Amaranthus tricolor and Setaria viridis in the invasive zone, the noninvasive zone and the noninvasive zone treated with extract from I. xanthiifolia leaf, and obtained I. xanthiifolia rhizosphere soil in the invasive zone. All wild plants were identified by Xu Yongqing. I. xanthiifolia (collection number: RQSB04100), A. tricolor (collection number: 831,030) and S. viridis (collection number: CF-0002-034) are all included in Chinese Virtual Herbarium ( https://www.cvh.ac.cn/index.php ). The soil bacterial diversity was analyzed based on the Illumina HiSeq sequencing platform. Subsequently, taxonomic analysis and Faprotax functional prediction were performed. RESULTS: The results showed that the leaf extract significantly reduced the diversity of indigenous plant rhizosphere bacteria. A. tricolor and S. viridis rhizobacterial phylum and genus abundances were significantly reduced under the influence of I. xanthiifolia or its leaf extract. The results of functional prediction showed that bacterial abundance changes induced by leaf extracts could potentially hinder nutrient cycling in native plants and increased bacterial abundance in the A. tricolor rhizosphere related to aromatic compound degradation. In addition, the greatest number of sensitive Operational Taxonomic Units (OTUs) appeared in the rhizosphere when S. viridis was in response to the invasion of I. xanthiifolia. It can be seen that A. tricolor and S. viridis have different mechanisms in response to the invasion of I. xanthiifolia. CONCLUSION: I. xanthiifolia leaves material has potential role in invasion by altering indigenous plant rhizosphere bacteria.

Impacts of calcium peroxide on phosphorus and tungsten releases from sediments.

In this study, CaO2 was used as a capping material to control the release of Phosphate (P) and tungsten (W) from the sediment due to its oxygen-releasing and oxidative properties. The results revealed significant decreases in SRP and soluble W concentrations after the addition of CaO2. The mechanisms of P and W adsorption by CaO2 were mainly chemisorption and ligand exchange mechanisms. In addition, the results showed significant increases in HCl-P and amorphous and poorly crystalline(oxyhydr)oxides bound W after the addition of CaO2. The highest reduction rates of sediment SRP and soluble W release were 37 and 43%, respectively. Furthermore, CaO2 can promote the redox of iron (Fe) and manganese (Mn). On the other hand, a significant positive correlation was observed between SRP/soluble W and soluble Fe (II) and between SRP/soluble W and soluble Mn, indicating that the effects of CaO2 on Fe and Mn redox play a crucial role in controlling P and W releases from sediments. However, the redox of Fe plays a key role in controlling sediment P and W release. Therefore, CaO2 addition can simultaneously inhibit sediment internal P and W release.

Regular Glucosamine Use May Have Different Roles in the Risk of Site-Specific Cancers: Findings from a Large Prospective Cohort.

BACKGROUND: Previous studies indicated that glucosamine supplements may have a general anticancer effect. This study aimed to assess whether the potential effect differs across different types of cancers in a large prospective cohort study. METHODS: All participants from the UK Biobank who were free of cancers and had complete information on glucosamine use at baseline were included and followed up from 2006 until 2021. Cox proportional hazards models were used to assess the associations between regular glucosamine use and different site-specific cancers. Subgroup analyses were performed to explore potential interactions. Several sensitivity analyses were conducted to assess the robustness of the main findings. RESULTS: A total of 450,207 eligible participants (mean age: 56.2 years; females: 53.3%) were included, of whom 84,895 (18.9%) reported regular glucosamine use at baseline. During a median of 12.5 years follow-up, glucosamine use was significantly associated with an increased risk of overall cancer [HR, 1.04; 95% confidence interval (CI), 1.01-1.06], skin cancer (HR, 1.11; 95% CI, 1.07-1.15), and prostate cancer (HR, 1.07; 95% CI, 1.01-1.13), and with a reduced risk of lung cancer (HR, 0.88; 95% CI, 0.79-0.97) after adjusting for potential confounders. Statistical interaction was observed for gender, age, and education for the association of glucosamine use with overall cancer risk (all Pinteraction < 0.027). These results remained unchanged in the sensitivity analyses. CONCLUSIONS: Regular glucosamine use was associated with lower risk of lung cancer but higher risk of skin cancer, prostate cancer, and overall cancer. IMPACT: The roles of glucosamine use potentially differ in the development of different site-specific cancers.

Gallic acid alleviates gastric precancerous lesions through inhibition of epithelial mesenchymal transition via Wnt/ß-catenin signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Gallic acid (GA) is a natural polyphenolic compound derived from Rhus chinensis Mill. with a variety of biological activities such as astringent sweat, cough, dysentery, hemostasis, and detoxification, and is widely used in China as a treatment for cough, bleeding, and gastrointestinal disorders. In recent years, the anticancer activity of GA has been demonstrated in a variety of cancers, affecting multiple cellular pathways associated with cancer onset, development and progression. AIM OF THE STUDY: To investigate the role and potential mechanism of GA on gastric precancerous lesions (GPL), the key turning point of gastritis to gastric cancer, with the aim of delaying, blocking or reversing the dynamic overall process of "inflammation-cancer transformation" and thus blocking GPL to prevent the development of gastric cancer. MATERIALS AND METHODS: In this study, we established N-Nitroso-N-methylurea (MNU)-induced GPL mice model and induced precancerous lesions of gastric cancer cells (MC), i.e. epithelial mesenchymal transition (EMT), in human gastric mucosal epithelial cells (GES-1) with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). We used conventional pathology, immunohistochemistry, RNA sequencing, Western blot and other techniques to study the therapeutic effect of GA on GPL and its possiblemechanism in vitro and in vivo. RESULTS: The results showed that compared with normal GES-1 cells, MC cells had the characteristics of malignant cells such as abnormal proliferation, invasion and metastasis, accompanied by decreased expression of EMT-related protein E-cadherin and increased expression of N-cadherin and Vimentin. GA can inhibit the malignant behavior of MC cell proliferation and induce its G0/G1 phase arrest, which is achieved by downregulating the Wnt/ß-catenin signaling pathway and thereby inhibiting the EMT process. However, when we incubated with the Wnt pathway activator (Wnt agonist 1), the effect of GA was reversed. Furthermore, analysis of human gastric specimens showed that activation of the Wnt/ß-catenin pathway was significantly associated with GPL pathological changes. Meanwhile, GA reversed MNU-induced intestinal metaplasia and partial dysplasia in GPL mice. CONCLUSION: Taken together, these results indicate that GA prevents the occurrence and development of GPL by inhibiting the Wnt/ß-catenin signaling pathway and then inhibiting the EMT process, which may become potential candidates for the treatment of GPL.

Efficacy and mechanisms of mobile application-delivered Acceptance and Commitment Therapy for posttraumatic stress disorder in China: Study protocol for a randomized controlled trial.

Background: As a result of the COVID-19 pandemic and its far-reaching impact, the prevalence of posttraumatic stress disorder (PTSD) symptoms is increasing significantly in China. Yet access to reliable and effective psychological treatment is still limited during the pandemic. The widespread adoption of mobile technologies may provide a new way to address this gap. In this research we will develop an Acceptance and Commitment Therapy (ACT) based intervention delivered by mobile application and will test its usability, efficacy, and mechanism of its effects in relieving PTSD symptoms. Methods: A total of 147 Chinese participants with a diagnosis of PTSD according to the Clinician Administered PTSD Scale (CAPS-5) will be randomly assigned to an intervention group (app-delivered ACT), an active comparison group (app-delivered mindfulness), or a waitlist group. Participants in the intervention group or comparison group will use their respective apps for one month. Online self-report questionnaires will be used to assess the primary outcome of PTSD symptoms and the secondary outcomes symptoms of depression, symptoms of anxiety, and posttraumatic growth. The potential mediating variable to be tested is psychological flexibility and its components. These assessments will be conducted at baseline, at five times during treatment, at the end of treatment, and at 1- and 3-month follow-ups. Discussion: As far as we know, this study is the first randomized controlled trial to investigate the usability, efficacy, and mechanism of an app-delivered ACT intervention for PTSD. Furthermore, the research will assess the effect of treatment in reducing dropout rates, explore effective therapeutic components, and investigate mechanisms of symptom change, which will be valuable in improving the efficacy and usability of PTSD interventions.Trial registration: ChiCTR2200058408.

Pull the plug: Anti-angiogenesis potential of natural products in gastrointestinal cancer therapy.

Gastrointestinal cancer (GIC), including gastric cancer and colorectal cancer, is a common malignant tumor originating from the gastrointestinal epithelium. Although the pathogenesis of GIC has not been fully elucidated, angiogenesis is recognized as the key pathological basis for the growth, invasion and metastasis of cancer cells, and GIC angiogenesis is closely related to vascular endothelial growth factor family, hypoxia-inducible factor family, fibroblast growth factor family and matrix metalloproteinase family. Recently, many natural products have shown a wide range of pharmacological biological activities against GIC. In this review, the effects and mechanisms of natural compounds on the angiogenesis of gastric and colorectal cancer were summarized. The results show that some natural compounds, especially gallic catechin gallate, astragaloside and curcumin, can effectively inhibit angiogenesis; the HIF-1α/VEGF, COX-2/PGE2, HGF/c-Met and PI3K/Akt/mTOR are involved in these inhibition effects. This review examines the anti-angiogenesis potential of natural products in the GIC treatment and provides clues to the development of vascular targeted agents.

ß-Elemene Promotes Apoptosis Induced by Hyperthermia via Inhibiting HSP70.

Thermotherapy has been presented as a promising strategy to be used as an effective nonsurgical technique for colorectal carcinoma. Although this strategy presents several advantages, including low toxicity and high repeatability, thermotherapy often needs to be combined with other therapies because residual tumor cells that survive hyperthermal treatment often lead to relapse. In this study, we evaluated the effects of ß-elemene, which has been proven to have the potential to reverse chemotherapy drug resistance, on promoting the antitumor effects of hyperthermia. ß-elemene treatment significantly promoted apoptosis after 2 hours of hyperthermia treatment and blocked cell cycle phases at G1/G0. ß-elemene also significantly decreased colony formation and tumor formation abilities after hyperthermia treatment. ß-elemene treatment significantly decreased HSP70, but not HSP90 or HSP27, induced by hyperthermia treatment without disturbing HSP70 mRNA. It was also found that ß-elemene decreased phosphorylated ERK1/2 induced by hyperthermia. Regain of HSP70 reversed ß-elemene-mediated apoptosis, indicating that ß-elemene may induce apoptosis by decreasing HSP70. Moreover, ß-elemene treatment significantly decreased invasion capacity by decreasing the EMT, which was induced by hyperthermia treatment. Taken together, our results offer a potential strategy for CRC therapy via the combination of hyperthermia and ß-elemene.

Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation.

BACKGROUND: Cancer stem cells (CSCs) are able to survive after cancer therapies, resulting in tumor progression and recurrence, as is seen in colorectal cancer. Therapies targeting CSCs are regarded as novel and promising strategies for efficiently eradicating tumors. Berberine, an isoquinoline alkaloid extracted from the Chinese herbal medicine Coptis chinensis, was found to have antitumor activities against colorectal cancer, without knowing whether it exerts inhibitory effects on colorectal CSCs and the potential mechanisms. METHODS: In this study, we examined the inhibitory roles of Berberine on CSCs derived from HCT116 and HT29 by culturing in serum-free medium. We also examined the effects of Berberine on m6A methylation via regulating fat mass and obesity-associated protein (FTO), by downregulating ß-catenin. RESULTS: We examined the effects of Berberine on the tumorigenicity, growth, and stemness of colorectal cancer stem-like cells. The regulatory effect of Berberine on N6-methyladenosine (m6A), an abundant mRNA modification, was also examined. Berberine treatment decreased cell proliferation by decreasing cyclin D1 and increasing p27 and p21 and subsequently induced cell cycle arrest at the G1/G0 phase. Berberine treatment also decreased colony formation and induced apoptosis. Berberine treatment transcriptionally increased FTO and thus decreased m6A methylation, which was reversed by both FTO knockdown and the addition of the FTO inhibitor FB23-2. Berberine induced FTO-related decreases in stemness in HCT116 and HT29 CSCs. Berberine treatment also increased chemosensitivity in CSCs and promoted chemotherapy agent-induced apoptosis. Moreover, we also found that Berberine treatment increased FTO by decreasing ß-catenin, which is a negative regulator of FTO. CONCLUSIONS: Our observation that Berberine effectively decreased m6A methylation by decreasing ß-catenin and subsequently increased FTO suggests a role of Berberine in modulating stemness and malignant behaviors in colorectal CSCs.

Generation of H2S from Thiol-Dependent NO Reactivity of Model [4Fe-4S] Cluster and Roussin's Black Anion.

Iron-sulfur clusters (Fe-S) have been well established as a target for nitric oxide (NO) in biological systems. Complementary to protein-bound studies, synthetic models have provided a platform to study what iron nitrosylated products and byproducts are produced depending on a controlled reaction environment. We have previously shown a model [2Fe-2S] system that produced a dinitrosyl iron complex (DNIC) upon nitrosylation along with hydrogen sulfide (H2S), another important gasotransmitter, in the presence of thiol, and hypothesized a similar reactivity pattern with [4Fe-4S] clusters which have largely produced inconsistent reaction products across biological and synthetic systems. Roussin's black anion (RBA), [Fe4(µ3-S)3(NO)7]-, is a previously established reaction product from synthetic [4Fe-4S] clusters with NO. Here, we present a new reactivity for the nitrosylation of a synthetic [4Fe-4S] cluster in the presence of thiol and thiolate. [Et4N]2[Fe4S4(SPh)4] (1) was nitrosylated in the presence of excess PhSH to generate H2S and an "RBA-like" intermediate that when further reacted with [NEt4][SPh] produced a {Fe(NO)2}9 DNIC, [Et4N][Fe(NO)2(SPh)2] (2). This "RBA-like" intermediate proved difficult to isolate but shares striking similarities to RBA in the presence of thiol based on IR υ(NO) stretching frequencies. Surprisingly, the same reaction products were produced when the reaction started with RBA and thiol. Similar to 1/NO, RBA in the presence of thiol and thiolate generates stoichiometric amounts of DNIC while releasing its bridging sulfides as H2S. These results suggest not only that RBA may not be the final product of [4Fe-4S] + NO but also that RBA has unprecedented reactivity with thiols and thiolates which may explain current challenges around identifying biological nitrosylated Fe-S clusters.

Cajanine promotes osteogenic differentiation and proliferation of human bone marrow mesenchymal stem cells.

BACKGROUND: Seed cells - mesenchymal stem cells (MSCs) - appear to be an attractive tool in the context of tissue engineering. Bone marrow represents the main source of MSCs for both experimental and clinical studies. However, the number limitation of bone marrow MSCs (BMSCs) and decreased function caused by proliferation make the search for adequate alternative sources of these cells for autologous and allogenic transplant necessary. OBJECTIVES: This study was aimed to investigate the roles of cajanine isolated from the extracts of Cajanus cajan L. Millsp. in the proliferation and differentiation of BMSCs, and to discover the mechanism of proliferation of BMSCs promoted by cajanine. MATERIAL AND METHODS: Bone marrow mesenchymal stem cells were cultured in high-glucose Dulbecco's Modified Eagle's Medium (DMEM) and osteogenic differentiation was induced by adding dexamethasone, ascorbic acid and ß-glycerophosphate supplements. Bone marrow MSCs were cultured in medium without cajanine or supplemented with cajanine. The information about the proliferation and osteogenic differentiation of BMSCs was collated. The osteogenic differentiation potential of BMSCs was also assessed at the 3rd passage by Von Kossa staining. To observe cell signal transduction changes of BMSCs after culturing them with cajanine for 24 h, the western blot analysis was performed to detect phosphorylated cell cycle proteins and activated cyclins. RESULTS: After osteogenic induction, the differentiation of BMSCs was accelerated by cajanine treatment. Osteogenesis markers were upregulated by cajanine treatment at both protein and mRNA levels. Cajanine obviously promoted the proliferation of BMSCs. After BMSCs were cultured with cajanine for 24 h, the cell cycle regulator proteins were phosphorylated or upregulated. CONCLUSIONS: Cajanine can promote the expansion efficiency of BMSCs, at the same time keeping their multi-differentiation potential. Cajanine can activate the cell cycle signal transduction pathway, thus inducing cells to enter the G1/S phase and accelerating cells entering the G2/M phase. This study can contribute to the development of cajanine-based drugs in tissue engineering.

The therapeutic effects of traditional Chinese medicine Fusu agent in LPS-induced acute lung injury model rats.

PURPOSE: Acute lung injury (ALI) is a common and fatal oxidative stress in the lung, mainly induced by endothelial injury and capillary leakage. In our previous study, "Fusu agent", a traditional Chinese medicine, was found to exert preventive effect on endothelial damage in lipopoly-saccharide (LPS)-induced ALI model rats partially via inhibiting heparanase1 (HPA1) activation and inhibiting the inflammatory factors. However, it is still unknown whether Fusu agent exerts its therapeutic effect in LPS-induced ALI model rats and its potential mechanism. MATERIALS AND METHODS: Rats were injected with LPS (3 mg/kg, intraperitoneally) to induced ALI, and the prepared Fusu agent was given (2, 4 or 6 g/kg) 2 hours after LPS challenge. Twenty-four or 48 hours after Fusu agent administration, the biochemical changes in the plasma and lung tissues and the morphological/histological changes in the lung associated with inflammation and injury were evaluated. Human umbilical vein endothelial cells (HUVECs) were employed to confirm the therapeutic effects of Fusu agent and investigate its mechanisms, that is, affecting ROS accumulation, mitochondrial transmembrane potential (MTP) maintenance and decreasing the expression levels of HPA1. RESULTS: Administration of Fusu agent obviously improved the lung injury and recovered vascular endothelium loss and injury. CD31 signal, which is a specific marker for endothelial vascular lesions, was decreased after Fusu agent treatment in LPS-induced ALI model rats, indicating its therapeutic effect against endothelial surface layer injury. Meanwhile, Fusu agent also decreased HPA1 expression and inflammatory responses. In vitro, Fusu agent-medicated serum decreased injury and cell death induced by LPS in HUVECs by stabilizing MTP and decreasing the leakage of lactate dehydrogenase. Consistently, Fusu agent-medicated serum downregulated HPA1 induced by LPS stimulation. CONCLUSION: These findings suggest that Fusu agent exerts its therapeutic effect in both LPS-induced ALI model rats and HUVECs potentially via suppressing HPA1 expression, and thus exerts prosurvival effect via maintaining MTP and attenuating cell injury.

Efficacy and safety of Sancai powder in patients with type 2 diabetes mellitus: a randomized controlled trial.

OBJECTIVE: To assess the efficacy and safety of Sancai powder in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with single oral metformin in a randomized controlled trial (RCT). METHODS: A total of 132 patients with T2DM were enrolled in the study, who only took metformin (500-1000 mg/day) for at least three months and with inadequate glycemic control (7.0% ≤ hemoglobin A1c ≤ 9.0% ) in the past three months. The patients stopped taking metformin with lifestyle interventions for three weeks, and 105 patients qualified for the program. They were randomly divided into the Sancai powder group and the metformin group (1500 mg/day). The follow-up period was for 12 weeks. Comparisons of several variables were analyzed. RESULTS: No significant differences were found between the two groups in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG) and 2 h post-meal glucose (2hPG), although they had decreased significantly (P < 0.01). Homeostasis model assessment of beta cell function index was significantly improved in Sancai powder group (P < 0.01), and there were significant differences in the changes of homeostasis model assessment of insulin resistance and insulin sensitivity index in the two groups (P < 0.05). Sancai powder significantly reduced triglyceride level (P < 0.05), although there was no significant difference in the body weight and body mass index in the two groups. CONCLUSION: In this 12-week study, Sancai powder could significantly reduce hemoglobin A1c, FPG and 2hPG levels, improved beta-cell function and insulin resistance of the T2DM inadequately controlled with metformin.